Novel compounds exhibiting impressive antiviral and/or antiparasitic properties have recently been described (Manfredi et al., J. Med. Chem., 4, 3402-3405, 1991; Bringmann et al., Angew.Chem. Int. Ed. Eng., 32, 1190-1191, 1993; Boyd et al., J. Med. Chem., 37, 1740-1745, 1994; Boyd et al. U.S. patent application Ser. No. 08/049,824; Bringmann et al., Tetrahedron, 50, 7807-7815, 1994a; Hallock et al., J. Org. Chem., 59, 6349-6355 1994b; Bringmann et al., Heterocycles, 39, 503-512 1994; Bringmann et al., Tetrahedron, 50, 9643-9648 1994c; Francois et al., Phytochemistry, 35, 1461-1464, 1994; Francois et al., U.S. patent application Ser. No. 08/195,547; Boyd et al., U.S. Pat. No. 5,409,938; concurrently filed Bringmann et al., U.S. patent application Ser. No. 08/279,291. These compounds are members of a general class known as naphthylisoquinoline alkaloids (Bringmann, The Alkaloids, Vol. 29 (Brossi, ed.), Academic Press, New York, 1986, pp. 141-184), and can further be characterized based on their structure as either monomeric alkaloids (or "monomers") or dimeric alkaloids (or "dimers").
Monomeric alkaloids include korupensamines or related monomeric naphthylisoquinoline alkaloids and derivatives thereof, which typically possess a C-8' to C-5 naphthalene/isoquinoline linkage, and non-korupensamine or other monomeric naphthylisoquinoline alkaloids and derivatives thereof, which typically lack a C-8' to C-5 naphthalene/isoquinoline linkage.
Dimeric alkaloids include michellamines, which, based on their molecular structure, are comprised of two monomeric alkaloids coupled together (e.g., two monomeric or molecular "halves"). Furthermore, a given michellamine may be either "homodimeric" (comprised of two monomeric halves which are the same) or "heterodimeric" (comprised of two monomeric halves which are different).
Dimeric naphthylisoquinoline alkaloids, as exemplified by the michellamines, have highly desirable and eminently useful medicinal properties that for the most part are distinct from the properties of the monomeric naphthylisoquinoline alkaloids which comprise their molecular halves. For example, the michellamines, such as michellamine B (Boyd et al., U.S. patent application Ser. No. 08/049,824; Boyd et al., 1994, supra), are highly effective inhibitors of the replication and resultant destructive effects of the human immunodeficiency virus (HIV) in human immune cells. The range of anti-HIV activity observed for these dimeric alkaloids is exceptionally broad, encompassing both the major viral types, HIV-1 and HIV-2, as well as diverse HIV strains, and can be observed in different host cells (Boyd et al., 1994, supra),
Moreover, the dimeric alkaloids would appear to comprise a novel antiviral drug class in that the mechanism of action of the michellamines is distinct from any mechanism previously described. Specifically, the mechanism involves at least two components: (1) an inhibition of the viral reverse transcriptase, and (2) an inhibition of the virus-cell and cell-cell fusion processes (McMahon et al., Antimicrob. Agents Chemother., submitted 39, 484-488 (1995)). This suggests that the dimeric alkaloids may prove effective not only in the prevention of nascent viral infection, but also in the prevention of the replication and spread of the virus in vivo and in the prevention of syncytia formation which has been observed in vitro and which may mediate the depletion of T4 immune cells which occurs in vivo.
In addition to the medicinally desirable properties of the dimeric alkaloids, they are also quite attractive from a pharmacological and toxicological standpoint. In vivo doses of michellamine B that are non-toxic result in a level of the drug in the blood which is well in excess of its effective antiviral concentration (Supko et al., Anal. Biochem., 216, 52-60, 1994; Supko et al., Antimicrob. Agents Chemother., submitted 39, 9-14 (1995)).
In contrast, the monomeric naphthylisoquinoline alkaloids appear to be devoid of anti-HIV activity. However, the monomeric alkaloids instead have potent antiparasitic properties as exhibited by their bacteriocidal activity against strains of malaria. In this respect, it is interesting to speculate that a trace of this antiparasitic activity may be imparted to the alkaloid dimer by its constituent monomeric halves, as a few of the dimeric naphthylisoquinoline alkaloids (e.g., the michellamines) also appear weakly antiparasitic (Boyd et al., U.S. Pat. No. 5,409,938; Francois et al., U.S. patent application Ser. No. 08/195,547; Francois et al., supra).
Unfortunately, attempts by researchers to maximally exploit the potential of the dimeric alkaloids through development of antiviral and antiparasitic therapy and unprecedented uses for the alkaloids have been hindered by the lack of significant access to the dimeric alkaloids. To date, the only known natural source of the dimeric alkaloids is the rare tropical vine Ancistrocladus korupensis of Central Africa (Thomas and Gereau, Novon, 3, 494-498, 1993; Boyd et al., 1994, supra; Hallock et al., 1994, supra). Monomeric naphthylisoquinoline alkaloids do not spontaneously combine or couple together to form the dimeric alkaloids, and a method of converting (e.g., coupling) monomeric alkaloids or derivatives thereof to form a dimeric alkaloid or derivative has heretofore been unknown. Indeed, the naturally occurring michellamines A, B, and C (Boyd et al., 1994, supra) and frustratingly simple derivatives prepared directly therefrom (see, e.g., Boyd et al., U.S. patent application Ser. No. 08/049,824) have been the only known dimeric naphthylisoquinoline alkaloids from any source. Alternative dimeric alkaloids, if such be obtained, might present particularly advantageous medicinal properties, such as increased potency, increased host range, increased range of therapeutic action, and the like.
Accordingly, it is an object of the present invention to provide methods of synthesizing known and new dimeric alkaloids, including homodimeric and heterodimeric naphthylisoquinoline alkaloids.
Correspondingly, it is another object of the present invention to provide new dimeric alkaloids. Such compounds have particular use as therapeutic agents, for instance, as antiviral and antiparasitic agents, as exemplified by the michellamines (Bringmann et al., Tetrahedron, 50, 9643-9648, 1994; concurrently filed Bringmann et al., U.S. patent application; Boyd et al., J. Med. Chem., 37, 1740-1745, 1994; Francois et al., U.S. patent application Ser. No. 08/195,547).
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.